Hypotension has been associated with rapid or bolus
intravenous infusion of LEVAQUIN® . LEVAQUIN® should be
infused slowly over 60 to 90 minutes, depending on dosage [see DOSAGE AND
ADMINISTRATION].

Crystalluria and cylindruria have been reported with
quinolones, including LEVAQUIN® . Therefore, adequate hydration of
patients receiving LEVAQUIN® should be maintained to prevent the
formation of a highly concentrated urine [see DOSAGE AND ADMINISTRATION].

Clinical Trial Experience

Because clinical trials are conducted under widely
varying conditions, adverse reaction rates observed in the clinical trials of a
drug cannot be directly compared to rates in the clinical trials of another
drug and may not reflect the rates observed in practice.

The data described below reflect exposure to LEVAQUIN® in 7537 patients in 29 pooled Phase 3 clinical trials. The population
studied had a mean age of 50 years (approximately 74% of the population was
< 65 years of age), 50% were male, 71% were Caucasian, 19% were Black.
Patients were treated with LEVAQUIN® for a wide variety of
infectious diseases [see INDICATIONS AND USAGE]. Patients received
LEVAQUIN® doses of 750 mg once daily, 250 mg once daily, or 500 mg
once or twice daily. Treatment duration was usually 3–14 days, and the mean
number of days on therapy was 10 days.

The overall incidence, type and distribution of adverse
reactions was similar in patients receiving LEVAQUIN® doses of 750
mg once daily, 250 mg once daily, and 500 mg once or twice daily.
Discontinuation of LEVAQUIN® due to adverse drug reactions occurred
in 4.3% of patients overall, 3.8% of patients treated with the 250 mg and 500
mg doses and 5.4% of patients treated with the 750 mg dose. The most common
adverse drug reactions leading to discontinuation with the 250 and 500 mg doses
were gastrointestinal (1.4%), primarily nausea (0.6%); vomiting (0.4%);
dizziness (0.3%); and headache (0.2%). The most common adverse drug reactions
leading to discontinuation with the 750 mg dose were gastrointestinal (1.2%),
primarily nausea (0.6%), vomiting (0.5%); dizziness (0.3%); and headache
(0.3%).

Adverse reactions occurring in ≥ 1% of LEVAQUIN®-treated
patients and less common adverse reactions, occurring in 0.1 to < 1% of
LEVAQUIN®-treated patients, are shown in Table 6 and Table 7,
respectively. The most common adverse drug reactions ( ≥ 3%) are nausea,
headache, diarrhea, insomnia, constipation, and dizziness.

In clinical trials using
multiple-dose therapy, ophthalmologic abnormalities, including cataracts and
multiple punctate lenticular opacities, have been noted in patients undergoing
treatment with quinolones, including LEVAQUIN®. The
relationship of the drugs to these events is not presently established.

Postmarketing Experience

Table 8 lists adverse reactions that have been identified
during post-approval use of LEVAQUIN®. Because these reactions are
reported voluntarily from a population of uncertain size, reliably estimating
their frequency or establishing a causal relationship to drug exposure is not
always possible.

DRUG INTERACTIONS

Chelation Agents: Antacids,
Sucralfate, Metal Cations, Multivitamins

LEVAQUIN® Tablets
and Oral Solution

While the chelation by divalent
cations is less marked than with other fluoroquinolones, concurrent administration
of LEVAQUIN® Tablets and Oral Solution with antacids containing
magnesium, or aluminum, as well as sucralfate, metal cations such as iron, and
multivitamin preparations with zinc may interfere with the gastrointestinal
absorption of levofloxacin, resulting in systemic levels considerably lower
than desired. Tablets with antacids containing magnesium, aluminum, as well as
sucralfate, metal cations such as iron, and multivitamin preparations with zinc
or didanosine may substantially interfere with the gastrointestinal absorption
of levofloxacin, resulting in systemic levels considerably lower than desired.
These agents should be taken at least two hours before or two hours after oral
LEVAQUIN® administration.

LEVAQUIN® Injection

There are no data concerning an interaction of
intravenous fluoroquinolones with oral antacids, sucralfate, multivitamins,
didanosine, or metal cations. However, no fluoroquinolone should be
co-administered with any solution containing multivalent cations, e.g.,
magnesium, through the same intravenous line [see DOSAGE AND ADMINISTRATION].

Warfarin

No significant effect of LEVAQUIN® on the peak
plasma concentrations, AUC, and other disposition parameters for R-and
S-warfarin was detected in a clinical study involving healthy volunteers.
Similarly, no apparent effect of warfarin on levofloxacin absorption and
disposition was observed. However, there have been reports during the
postmarketing experience in patients that LEVAQUIN® enhances the effects
of warfarin. Elevations of the prothrombin time in the setting of concurrent
warfarin and LEVAQUIN® use have been associated with episodes of
bleeding. Prothrombin time, International Normalized Ratio (INR), or other
suitable anticoagulation tests should be closely monitored if LEVAQUIN® is
administered concomitantly with warfarin. Patients should also be monitored for
evidence of bleeding [see ADVERSE REACTIONS; PATIENT INFORMATION].

Non-Steroidal Anti-Inflammatory Drugs

The concomitant administration of a non-steroidal
anti-inflammatory drug with a fluoroquinolone, including LEVAQUIN® ,
may increase the risk of CNS stimulation and convulsive seizures [see WARNINGS AND PRECAUTIONS].

Theophylline

No significant effect of LEVAQUIN® on the
plasma concentrations, AUC, and other disposition parameters for theophylline
was detected in a clinical study involving healthy volunteers. Similarly, no
apparent effect of theophylline on levofloxacin absorption and disposition was
observed. However, concomitant administration of other fluoroquinolones with
theophylline has resulted in prolonged elimination half-life, elevated serum
theophylline levels, and a subsequent increase in the risk of
theophylline-related adverse reactions in the patient population. Therefore,
theophylline levels should be closely monitored and appropriate dosage
adjustments made when LEVAQUIN® is co-administered. Adverse
reactions, including seizures, may occur with or without an elevation in serum
theophylline levels [see WARNINGS AND PRECAUTIONS].

Cyclosporine

No significant effect of LEVAQUIN® on the peak
plasma concentrations, AUC, and other disposition parameters for cyclosporine
was detected in a clinical study involving healthy volunteers. However,
elevated serum levels of cyclosporine have been reported in the patient
population when co-administered with some other fluoroquinolones. Levofloxacin
Cmax and ke were slightly lower while Tmax and t½ were slightly longer in the
presence of cyclosporine than those observed in other studies without
concomitant medication. The differences, however, are not considered to be
clinically significant. Therefore, no dosage adjustment is required for
LEVAQUIN® or cyclosporine when administered concomitantly.

Digoxin

No significant effect of LEVAQUIN® on the peak
plasma concentrations, AUC, and other disposition parameters for digoxin was
detected in a clinical study involving healthy volunteers. Levofloxacin
absorption and disposition kinetics were similar in the presence or absence of
digoxin. Therefore, no dosage adjustment for LEVAQUIN® or digoxin is
required when administered concomitantly.

Probenecid And Cimetidine

No significant effect of probenecid or cimetidine on the
Cmax of levofloxacin was observed in a clinical study involving healthy
volunteers. The AUC and t½ of levofloxacin were higher while CL/F and CLR were
lower during concomitant treatment of LEVAQUIN® with probenecid or
cimetidine compared to LEVAQUIN® alone. However, these changes do
not warrant dosage adjustment for LEVAQUIN® when probenecid or cimetidine
is co-administered.

Interactions With Laboratory Or Diagnostic Testing

Some fluoroquinolones, including LEVAQUIN®,
may produce false-positive urine screening results for opiates using
commercially available immunoassay kits. Confirmation of positive opiate
screens by more specific methods may be necessary.